UniProt functional annotation for P19438



	UniProt functional annotation for P19438

UniProt code: P19438.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Receptor for TNFSF2/TNF-alpha and homotrimeric TNFSF1/lymphotoxin-alpha. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. Contributes to the induction of non-cytocidal TNF effects including anti-viral state and activation of the acid sphingomyelinase.

Subunit: Binding of TNF to the extracellular domain leads to homotrimerization. The aggregated death domains provide a novel molecular interface that interacts specifically with the death domain of TRADD. Various TRADD-interacting proteins such as TRAFS, RIPK1 and possibly FADD, are recruited to the complex by their association with TRADD. This complex activates at least two distinct signaling cascades, apoptosis and NF-kappa-B signaling. Interacts with BAG4, BABAM2, FEM1B, GRB2, SQSTM1 and TRPC4AP (PubMed:10356400, PubMed:10359574, PubMed:10542291, PubMed:15465831, PubMed:8387891, PubMed:9915703). Interacts directly with NOL3 (via CARD domain); inhibits TNF-signaling pathway (By similarity). Interacts with SH3RF2, TRADD and RIPK1. SH3RF2 facilitates the recruitment of RIPK1 and TRADD to TNFRSF1A in a TNF- alpha-dependent process (PubMed:24130170). Interacts with PGLYRP1; this interaction is important for cell death induction (PubMed:26183779). Interacts (via death domain) with MADD (via death domain) (PubMed:9115275). {ECO:0000250|UniProtKB:P25118, ECO:0000269|PubMed:10356400, ECO:0000269|PubMed:10359574, ECO:0000269|PubMed:10542291, ECO:0000269|PubMed:15465831, ECO:0000269|PubMed:24130170, ECO:0000269|PubMed:26183779, ECO:0000269|PubMed:8387891, ECO:0000269|PubMed:9115275, ECO:0000269|PubMed:9915703}.

Subunit: (Microbial infection) Interacts with mumps virus protein SH; this interaction inhibits downstream NF-kappa-B pathway activation. {ECO:0000269|PubMed:28659487}.

Subunit: (Microbial infection) Interacts with HCV core protein. {ECO:0000269|PubMed:9557650}.

Subunit: (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL138. {ECO:0000269|PubMed:21976655}.

Subunit: (Microbial infection) Interacts with host TNFRSF1A; this interaction leads to the stimulation of both surface expression and shedding of TNFRSF1A. {ECO:0000269|PubMed:15247912, ECO:0000269|PubMed:16709567}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:22801493}; Single-pass type I membrane protein {ECO:0000269|PubMed:22801493}. Golgi apparatus membrane {ECO:0000269|PubMed:22801493}; Single-pass type I membrane protein {ECO:0000269|PubMed:22801493}. Secreted {ECO:0000269|PubMed:22801493}. Note=A secreted form is produced through proteolytic processing.

Subcellular location: [Isoform 4]: Secreted. Note=Lacks a Golgi- retention motif, is not membrane bound and therefore is secreted.

Domain: The domain that induces A-SMASE is probably identical to the death domain. The N-SMASE activation domain (NSD) is both necessary and sufficient for activation of N-SMASE.

Domain: Both the cytoplasmic membrane-proximal region and the C- terminal region containing the death domain are involved in the interaction with TRPC4AP. {ECO:0000250}.

Ptm: The soluble form is produced from the membrane form by proteolytic processing.

Ptm: (Microbial infection) Glycosylated at Arg-376 by enteropathogenic E.coli protein NleB1 and S.typhimurium protein Ssek3: arginine GlcNAcylation prevents homotypic/heterotypic death domain interactions. {ECO:0000269|PubMed:32766249, ECO:0000305|PubMed:23955153}.

Disease: Periodic fever, familial, autosomal dominant (FPF) [MIM:142680]: A hereditary periodic fever syndrome characterized by recurrent fever, abdominal pain, localized tender skin lesions and myalgia. Reactive amyloidosis is the main complication and occurs in 25% of cases. {ECO:0000269|PubMed:10199409, ECO:0000269|PubMed:10902757, ECO:0000269|PubMed:11443543, ECO:0000269|PubMed:13130484, ECO:0000269|PubMed:14610673}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Multiple sclerosis 5 (MS5) [MIM:614810]: A multifactorial, inflammatory, demyelinating disease of the central nervous system. Sclerotic lesions are characterized by perivascular infiltration of monocytes and lymphocytes and appear as indurated areas in pathologic specimens (sclerosis in plaques). The pathological mechanism is regarded as an autoimmune attack of the myelin sheath, mediated by both cellular and humoral immunity. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia and bladder dysfunction. Genetic and environmental factors influence susceptibility to the disease. {ECO:0000269|PubMed:22801493}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. An intronic mutation affecting alternative splicing and skipping of exon 6 directs increased expression of isoform 4 a transcript encoding a C-terminally truncated protein which is secreted and may function as a TNF antagonist.

Miscellaneous: [Isoform 4]: Disease-associated isoform. Isoform 4 splicing pattern is driven by a variation in the exon 6/intron 6 boundary region that alters exon 6 splicing. Exon 6 skipping introduces a frameshift and the translation of a protein lacking the intracellular, the transmembrane and part of the extracellular domain. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Receptor for TNFSF2/TNF-alpha and homotrimeric TNFSF1/lymphotoxin-alpha. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. Contributes to the induction of non-cytocidal TNF effects including anti-viral state and activation of the acid sphingomyelinase.


Subunit:		Binding of TNF to the extracellular domain leads to homotrimerization. The aggregated death domains provide a novel molecular interface that interacts specifically with the death domain of TRADD. Various TRADD-interacting proteins such as TRAFS, RIPK1 and possibly FADD, are recruited to the complex by their association with TRADD. This complex activates at least two distinct signaling cascades, apoptosis and NF-kappa-B signaling. Interacts with BAG4, BABAM2, FEM1B, GRB2, SQSTM1 and TRPC4AP (PubMed:10356400, PubMed:10359574, PubMed:10542291, PubMed:15465831, PubMed:8387891, PubMed:9915703). Interacts directly with NOL3 (via CARD domain); inhibits TNF-signaling pathway (By similarity). Interacts with SH3RF2, TRADD and RIPK1. SH3RF2 facilitates the recruitment of RIPK1 and TRADD to TNFRSF1A in a TNF- alpha-dependent process (PubMed:24130170). Interacts with PGLYRP1; this interaction is important for cell death induction (PubMed:26183779). Interacts (via death domain) with MADD (via death domain) (PubMed:9115275). {ECO:0000250\|UniProtKB:P25118, ECO:0000269\|PubMed:10356400, ECO:0000269\|PubMed:10359574, ECO:0000269\|PubMed:10542291, ECO:0000269\|PubMed:15465831, ECO:0000269\|PubMed:24130170, ECO:0000269\|PubMed:26183779, ECO:0000269\|PubMed:8387891, ECO:0000269\|PubMed:9115275, ECO:0000269\|PubMed:9915703}.
Subunit:		(Microbial infection) Interacts with mumps virus protein SH; this interaction inhibits downstream NF-kappa-B pathway activation. {ECO:0000269\|PubMed:28659487}.
Subunit:		(Microbial infection) Interacts with HCV core protein. {ECO:0000269\|PubMed:9557650}.
Subunit:		(Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL138. {ECO:0000269\|PubMed:21976655}.
Subunit:		(Microbial infection) Interacts with host TNFRSF1A; this interaction leads to the stimulation of both surface expression and shedding of TNFRSF1A. {ECO:0000269\|PubMed:15247912, ECO:0000269\|PubMed:16709567}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:22801493}; Single-pass type I membrane protein {ECO:0000269\|PubMed:22801493}. Golgi apparatus membrane {ECO:0000269\|PubMed:22801493}; Single-pass type I membrane protein {ECO:0000269\|PubMed:22801493}. Secreted {ECO:0000269\|PubMed:22801493}. Note=A secreted form is produced through proteolytic processing.
Subcellular location:		[Isoform 4]: Secreted. Note=Lacks a Golgi- retention motif, is not membrane bound and therefore is secreted.
Domain:		The domain that induces A-SMASE is probably identical to the death domain. The N-SMASE activation domain (NSD) is both necessary and sufficient for activation of N-SMASE.
Domain:		Both the cytoplasmic membrane-proximal region and the C- terminal region containing the death domain are involved in the interaction with TRPC4AP. {ECO:0000250}.
Ptm:		The soluble form is produced from the membrane form by proteolytic processing.
Ptm:		(Microbial infection) Glycosylated at Arg-376 by enteropathogenic E.coli protein NleB1 and S.typhimurium protein Ssek3: arginine GlcNAcylation prevents homotypic/heterotypic death domain interactions. {ECO:0000269\|PubMed:32766249, ECO:0000305\|PubMed:23955153}.
Disease:		Periodic fever, familial, autosomal dominant (FPF) [MIM:142680]: A hereditary periodic fever syndrome characterized by recurrent fever, abdominal pain, localized tender skin lesions and myalgia. Reactive amyloidosis is the main complication and occurs in 25% of cases. {ECO:0000269\|PubMed:10199409, ECO:0000269\|PubMed:10902757, ECO:0000269\|PubMed:11443543, ECO:0000269\|PubMed:13130484, ECO:0000269\|PubMed:14610673}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Multiple sclerosis 5 (MS5) [MIM:614810]: A multifactorial, inflammatory, demyelinating disease of the central nervous system. Sclerotic lesions are characterized by perivascular infiltration of monocytes and lymphocytes and appear as indurated areas in pathologic specimens (sclerosis in plaques). The pathological mechanism is regarded as an autoimmune attack of the myelin sheath, mediated by both cellular and humoral immunity. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia and bladder dysfunction. Genetic and environmental factors influence susceptibility to the disease. {ECO:0000269\|PubMed:22801493}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. An intronic mutation affecting alternative splicing and skipping of exon 6 directs increased expression of isoform 4 a transcript encoding a C-terminally truncated protein which is secreted and may function as a TNF antagonist.
Miscellaneous:		[Isoform 4]: Disease-associated isoform. Isoform 4 splicing pattern is driven by a variation in the exon 6/intron 6 boundary region that alters exon 6 splicing. Exon 6 skipping introduces a frameshift and the translation of a protein lacking the intracellular, the transmembrane and part of the extracellular domain. {ECO:0000305}.